Cerebrovascular disease can be groupified into a hemorrhagic group and an ischemic group. The hemorrhagic group typically comprises subarachnoid hemorrhage arising from aneurysmal rupture, hypertensive cerebral hemorrhage, and head trauma. Subarachnoid hemorrhage entails a delayed vasospasm of the major cerebral arteries and may lead to vascular constriction disorders and sometimes to death. The ischemic group is represented by cerebral infarction and transient ischemic attack (TIA). The vascular disorder and neuronal injury caused by infarction or hemorrhage may lead to dyskinesia such as numbness or motor paralysis of the limbs and neurologic and mental dysfunctions in the acute through chronic stage, with disturbance of consciousness and death ensuing in severe cases.
For the treatment of such cerebrovascular diseases, antithrombotics and enhancers of cerebral circulation and metabolism have been used to this day. However, few drugs are available which inhibit this fatal cerebral vasospasm or the neuronal injury leading to dementia and there exists a pressing need for an effective therapeutic agent.
By way of illustration, as subarachnoid hemorrhage takes place, narrowing of the vascular lumen persisting for several weeks is induced in the major cerebral arteries in 4.about.5 days following the bleeding event. This phenomenon is known as cerebral vasospasm and once the ultimate ischemia triggers the onset of neurological symptoms, the functional prognosis and, at times, even the vital prognosis of the case are seriously influenced.
As the therapeutic drug for cerebral vasospasm subsequent to subarachnoid hemorrhage, fasudil [hexahydro-1-(5-isoquinolinylsulfonyl)-1H-1,4-diazepine] hydrochloride is the only drug that is used clinically today (Japanese Kokai Tokkyo Koho S61-227581).
Aside from the above drug, it is known that compounds having an isoquinoline ring substituted by cyclic aminosulfonyl in its 5-position are useful as cerebrovascular drugs (vasodilators, enhancers of cerebral circulation and metabolism, antianginal drugs, prophylactic and therapeutic drugs for cerebrovascular or cardiovascular thrombosis, and prophylactic and therapeutic drugs for hypertension) [Japanese Kokai Tokkyo Koho S57-156463, S58-121279, and S61-227581].
Not known, however, is a compound such that its isoquinoline skeleton has been substituted by a cyclic aminosulfonyl group in its 5-positon and further substituted in its 4-position.